Enantioselective Synthesis of the Excitatory Amino Acid (1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic Acid Daniel M. Bradley,† Renameditswe Mapitse,† Nicholas M. Thomson,‡ and Christopher J. Hayes*,† The School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, U.K., and Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, U.K.
[email protected] Received May 2, 2002
An enantioselective synthesis of the R,R-dialkyl-R-amino acid (1S,3R)-ACPD has been achieved using an alkylidene carbene 1,5-CH insertion reaction as a key step. The ketone cyclization precursor was synthesized from Garner’s aldehyde in high yield via a Wittig homologation and subsequent catalytic hydrogenation. Treatment of the ketone with 1.2 equiv of lithio(trimethylsilyl)diazomethane in THF resulted in the formation of the corresponding cyclopentene-containing CH-insertion product in 62-69% yield in high enantiomeric excess. Subsequent functional group manipulation allowed the synthesis of the amino acid (1S,3R)-ACPD to be completed. Introduction (1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic acid (ACPD, 1) is a conformationally restricted analogue of L-glutamic acid, which is the major neurotransmitter in the mammalian central nervous system (CNS). Glutamate receptors can be divided into two major classes: (1) the ionotropic (iGluRs) and (2) the metabotropic (mGluRs) glutamate receptors. Compound 1 selectively agonizes the latter.1 The use of 1 as a tool in the study of glutamate receptor function and its potential use as a therapeutic agent for neurodegenerative disorders have led a number of research groups to develop stereoselective syntheses of this material (Figure 1). On the basis of the previously reported route of Connors and Ross,2a and then later Meister et al.,2b Curry et al. synthesized all four stereoisomers of 1 from (()-3oxocyclopentanecarboxylic acid 3 by brucine salt mediated resolution, followed by construction of the R,Rdialkyl-R-amino acid moiety using a Bucherer-Bergs/ Strecker-type transformation.2c Azerad et al. subsequently showed that esters of the key oxocyclopentanecarboxylic acid 3 could be resolved using a microbial reduction of the cyclopentanone, followed by separation and oxidation of the resulting cyclopentanol.2d Using a conceptually different approach, Ma et al. completed an enantioselective synthesis of 1 starting from L-malic acid 4.2e In this †
University of Nottingham. Pfizer Global Research and Development. (1) (a) Kno¨pfel, T.; Kuhn, R.; Allgeier, H. J. Med. Chem. 1995, 38, 1417. (b) Kno¨pfel, T.; Gasparini, F. Drug Discovery Today 1996, 1, 103. (2) (a) Connors, T. A.; Ross, W. C. J. J. Chem. Soc. 1960, 2119. (b) Stephani, R. A.; Rowe, W. B.; Gass, J. D.; Meister, A. Biochemistry 1972, 11, 4094. (c) Curry, K.; Peet, M. J.; Magnuson, D. S. K.; McLennan, H. J. Med. Chem. 1988, 31, 864. (d) Trigalo, F.; Buisson, D.; Azerad, R. Tetrahedron Lett. 1988, 29, 6109. (e) Ma, D.; Ma, J.; Dai, L. Tetrahedron: Asymmetry 1997, 8, 825; (f) Hodgson, D. M.; Thompson, A. J.; Wadman, S. Tetrahedron Lett. 1998, 39, 3357. (g) Hodgson, D. M.; Thompson, A. J.; Wadman, S.; Keats, C. J. Tetrahedron 1999, 55, 10815. ‡
FIGURE 1. Previous syntheses of (1S,3R)-ACPD 1.
synthesis, the (1S)-stereocenter was introduced via a Curtius rearrangement and the 3-carboxylic acid substituent was installed via a displacement of the mesylate 2 with cyanide, followed by hydrolysis. The fact that the cyanide displacement only proceeded with 40% de seemed to indicate that some SN1 substitution or subsequent epimerization was occurring during this transformation. Recently, Hodgson et al. used an asymmetric carbamatedirected hydroboration of 5 to synthesize 2 in moderate enantiomeric excess2f,g and were able to complete a synthesis of 1 via a route similar to that described by Ma. We have previously reported a method for the construction of the cyclopentane-containing R,R-dialkyl-Ramino acid (1S,3R)-2,5-methanoleucine based upon an alkylidene carbene 1,5-CH insertion reaction,3 and we now wish to report a full account of our studies on the application of this methodology to a short and novel enantioselective synthesis of (1S,3R)-ACPD 1. Results and Discussion Our retrosynthetic analysis of 1 is shown in Scheme 1. Based upon our previous studies, we planned to access (3) Gabaitsekgosi, R.; Hayes, C. J. Tetrahedron Lett. 1999, 40, 7713.
10.1021/jo025892v CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/05/2002
J. Org. Chem. 2002, 67, 7613-7617
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Bradley et al. SCHEME 1
SCHEME 2a
a Reagents: (i) HgSO , H SO , MeOH/H O (65%); (ii) Br , 4 2 4 2 2 MeOH; (iii) TFA/H2O (90%, two steps); (iv) PPh3, PhMe, then KOH, H2O (60%); (v) 9, CH2Cl2 (91%); (vi) Pd/C, H2, EtOAc, 2 h (95%); (vii) Pd/C, H2, 18 h (82%); (viii) TBSOTf, Et3N, DMAP, DMF (83%).
the dicarboxylic acid from the protected diol 6 using standard functional group interconversions. The desired (3R)-stereochemistry in 1 could be introduced by catalytic hydrogenation of 6, with the bulky Boc protecting group blocking one face of the cyclic olefin. We anticipated that the key cyclopentene 6 could be accessed via a 1,5-CH insertion reaction of a suitably functionalized alkylidene carbene 7, which in turn could be generated from the corresponding ketone 11 by treatment with lithio(trimethylsilyl)diazomethane 8.4 The cyclization precursor 11 was further disconnected to reveal Garner’s aldehyde 9 and the phosphorane 10 as possible starting materials. As multigram quantities of Garner’s aldehyde 95a were readily available using the modified procedure as described by Taylor et al.,5b our synthetic attention first turned to the elaboration of the alkoxy-substituted phosphorane 10. Following literature precedent,6 alkylation of benzyl alcohol with propargyl bromide gave the desired ether 12, and mercuric ion-mediated hydrolysis of the alkyne then afforded the corresponding methyl ketone 13 in acceptable yield (Scheme 2). Bromination of 13 afforded the desired bromomethyl ketone 14 along with significant amounts of its dimethoxy ketal derivative, but acid-mediated hydrolysis of the crude reaction mixture (4) (a) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66, 143. (b) Taber, D. F.; Han, Y.; Incarvito, C. D.; Rheingold, A. L. J. Am. Chem. Soc. 1998, 120, 13285. (c) Taber, D. F.; Meagley, R. P.; Walter, R. J. Org. Chem. 1994, 59, 6014. (d) Taber, D. F.; Meagley, R. P.; Doren, D. J. J. Org. Chem. 1996, 61, 5723. (e) Ohira, S.; Ishi, S.; Shinohara, K.; Nozaki, H. Tetrahedron Lett. 1990, 31, 1039. (f) Gilbert, J. C.; Giamalva, D. H.; Baze, M. E. J. Org. Chem. 1985, 50, 2557. (5) (a) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361 (b) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. Synthesis 1998, 1707. (6) Boger, D. L.; Palanki, M. S. S. J. Am. Chem. Soc. 1992, 114, 9318.
7614 J. Org. Chem., Vol. 67, No. 22, 2002
allowed 14 to be isolated in good overall yield. With multigram quantities of 14 in hand, the synthesis of the phosphorane 16 was completed using a standard twostep procedure involving displacement of the bromide with triphenylphosphine, followed by generation of the ylide with KOH.7 Pleasingly, the phosphorane 16 underwent smooth Wittig-type olefination with Garner’s aldehyde to afford the unsaturated ketone 15 (>20:1, E/Z) in excellent yield. Catalytic hydrogenation over palladium on carbon then afforded the hydroxymethyl ketone 18. We found that reduction of the olefin in 15 was much faster than hydrogenolysis of the benzyloxy group, and the intermediate saturated benzyloxymethyl ketone 17 could be isolated if desired. For the synthesis of ACPD, exchange of the benzyl protecting group was deemed necessary as the benzylic methylene present in 17 would provide a competitive site for 1,5-CH insertion of the alkylidene carbene intermediate. To complete the synthesis of the cyclization precursor 19, all that remained was TBSprotection of the hydroxymethyl ketone 18. To our chagrin, TBS-protection of 18 proved to be a nontrivial operation and a number of alternative procedures had to be examined before suitable conditions were found. For example, treatment of a solution of 18 in DMF with TBSCl in the presence of imidazole followed by aqueous workup resulted in the isolation of only small amounts of 19, with the starting material 18 accounting for the mass balance. Deprotonation of the R-hydroxy ketone 18 with LDA in THF or DMF before addition of TBS-Cl and aqueous workup resulted in the same low yield of 19. Fortunately, the desired cyclization precursor 19 could be accessed conveniently by using TBSOTf in the presence of Et3N and DMAP. We found that after stirring for 1 h at room temperature, the crude reaction mixture could be loaded directly onto a SiO2 gel flash column, and the desired product 19 could be isolated in high yield and purity by elution with petroleum ether/Et2O (6:1). Subsequent investigations revealed that the silyloxymethyl ketone 19 was very susceptible to mildly basic hydrolysis, and the nature of this reactivity is currently being investigated. Although we were able to access the desired cyclization precursor 19 using the chemistry described above, we were somewhat unhappy with several aspects of the route and we decided to address these by developing a more efficient second-generation synthesis. Upon examination of the synthesis of 19 (vide supra), it was clear that both the effort required to synthesize the phosphorane 16 on large scale, and a rather frustrating benzyl to TBS protecting group swap, were making it difficult to access multigram quantities of 19. We felt it would be much better if we could synthesize an ylide (e.g., 21) with the desired TBS protecting group already in place and to do this in a much more convergent manner. We therefore decided to examine methods for the synthesis of the revised ylide 21. We felt that the route used to synthesize the phosphorane 16 would be unsuitable, as it was quite lengthy and the TBS-protecting group required was unlikely to survive the harshly acidic conditions used. In principle we felt it should be possible to access 21 directly by acylation of methylenetriphenylphosphorane (7) For details of the synthesis of 16 see the Supporting Information.
Synthesis of (1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic Acid SCHEME 3
with methyl glycolate 20.8 To test this new route, methyl glycolate was first protected (TBSCl, imidazole, DMF) to afford 20.9 Pleasingly, we found that the desired stabilized ylide 21 could be accessed in good yield (50-69%) on a 60-70 g scale, by the dropwise addition of 20 to 2 equiv of a cool (0 °C) solution of methylenetriphenylphosphorane in THF. The ylide 21 could be purified by flash column chromatography if required, but we found that on a large scale, washing the solid product with EtOAc was sufficient to provide material of adequate purity for further transformations. We also found that the benzyloxy-substituted phosphorane 16 could be accessed in a similar manner by treatment of methylenetriphenylphosphorane with the commercially available acid chloride 23 or the methyl ester derivative 22 (Scheme 3). Gratifyingly, the new phosphorane 21 underwent smooth Wittig reaction with Garner’s aldehyde to afford the corresponding enone 24, and catalytic hydrogenation proceeded cleanly to complete the new route to the desired cyclization precursor 19. To our pleasure, and in accord with our previously reported model study,3 reaction of 19 with lithio(trimethylsilyl)diazomethane in THF (-78 f 0 °C) gave the desired cyclopentene product 27 in 62-69% yield. We were unable to determine the enantiomeric excess of 27 directly and further derivatization was required. Thus dihydroxylation of 27 using the Upjohn conditions10 afforded the corresponding diol (+)-25 (94%) in high diasteromeric excess (>95% de by 1 HNMR of the crude reaction mixture). A racemic sample of 25 was prepared from (()-Garner’s aldehyde 9 using an identical synthetic route to that described above, and this was used as a reference sample for subsequent % ee determinations. Using this sample, the diol (+)-25 was shown to have >95% ee by chiral HPLC analysis (Chiralpak AD, 8:92 IPA/hexane), thus confirming the stereochemical integrity of the quaternary stereocenter in the insertion product 27. Having installed the (1S)-quaternary center, the remaining (3R)-stereochemistry was then introduced via catalytic hydrogenation (Pd, 10% on carbon) to afford 26 as the predominant diastereoisomer (10:1, 3R/3S) (Scheme 4). Unfortunately we were unable to separate the minor diasteroisomer from this mixture, and the 10:1 mixture of (3R/3S) isomers was carried through the remaining transformations. With all of the C-C bond formations completed, all that remained to finish the synthesis of 1 was a series of standard functional group interconversions. First of all, (8) (a) Wittig, G.; Scho¨llkopf, U. Chem. Ber. 1954, 87, 1318. (b) Bestmann, H. J. Tetrahedron Lett. 1960, (4), 7. (c) Bestmann, H. J.; Arnason, B. Tetrahedron Lett. 1961, 455. (d) Trippett, S.; Walker, D. M. J. Chem. Soc. 1961, 1266. (e) Bestmann, H. J. Angew. Chem., Int Ed. Engl. 1962, 1, 270. (f) Chopard, P. A.; Searle, R. J. G.; Devitt, F. H. J. Org. Chem. 1965, 30, 1015. (9) Mukaiyama, T.; Teruaki, I.; Iwadare, H.; Saitoh, M.; Toshihiro, N.; Naoto, O.; Sakoh, H.; Nishmura, K.; Tani, Y.-I.; Hasegawa, M.; Yamada, K.; Saitoh, K. Chem. Eur. J. 1999, 5, 121. (10) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 17, 1973
SCHEME 4a
a Reagents: (i) CH Cl , rt (87%); (ii) Pd/C, H , EtOAc (80%); 2 2 2 (iii) TMSCHN2, BuLi, THF (-78 °C), then 19 (-78 f 0 °C) (69%); (iv) OsO4, NMO, Me2CO/H2O (94%); (v) Pd/C, H2, EtOAc; (vi) HF/ MeCN (81%, two steps); (vii) RuCl3, NaIO4, CCl4, MeCN, H2O; (viii) HCl, EtOAc (49%, two steps).
selective deprotection of 26 with HF/MeCN afforded the corresponding diol 28 in good yield. Oxidation of this diol with RuCl3/NaIO411 next afforded N-Boc-protected ACPD 29, which was sufficiently pure to use in the final deprotection step without further purification. Exposure of 29 to HCl in EtOAc effected removal of the Boc protecting group, and evaporation of the volatiles resulted in the production of (1S,3R)-ACPD as its HCl salt (49%, from 28). Ion exchange chromatography (Dowex 50 × 8-200, 2 M NH3(aq)), of this salt then afforded (1S,3R)ACPD 1 as a white solid. The data recorded (mp, 1H NMR, 13C NMR) for our synthetic material matched that previously reported for ACPD 1, and copies of the 1H and 13 C NMR data are provided in the Supporting Information.12 In summary, we have shown that the excitatory amino acid (1S,3R)-ACPD 1 can be synthesized from Garner’s aldehyde 9 in seven steps using a conceptually novel approach. An alkylidene carbene 1,5-CH insertion reaction was used as a key step to introduce the (1R)quaternary center with a high degree of stereocontrol, and the cyclopentene-containing CH-insertion product 27 should prove to be a valuable building block in the synthesis of other glutamate analogues. These and other studies in this area will be reported in due course.
Experimental Section Starting materials were obtained from commercial suppliers and used without further purification unless otherwise stated. All reactions were performed in flame-dried apparatus under an atmosphere of nitrogen at room temperature unless otherwise stated. CH2Cl2 was distilled from CaH2, and THF from Na/benzophenone ketyl under nitrogen. Flash chromatography (11) (a) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46, 3936. (b) Chakraborty, T. K.; Ghosh, S.; Jayaprakash, S.; Sharma, J. A. R. P.; Ravikanth, V.; Diwan, P. V.; Nagaraj, R.; Kunwar, A. C. J. Org. Chem. 2000, 65, 6441. (12) For NMR data of an authentic sample of 1, see: Larue, V.; Gharbi-Benarous, J.; Acher, F.; Valle, G.; Crisma, M.; Toniolo, C.; Azerad, R.; Girault, J.-P. J. Chem. Soc., Perkin Trans. 2 1995, 1111. We believe that the slight difference between our observed optical rotation for 1 ([R]29D -5.6 (c 1.3, H2O)) and that previously reported in the literature2c ([R]29D -6.9 (c 1.0, H2O)) is due to the presence of 5-10% of the (1S,3S)-diasteroisomer of 1 ([R]20D +8.4 (c 1.0, H2O)).
J. Org. Chem, Vol. 67, No. 22, 2002 7615
Bradley et al. was carried out using Merck silica gel 60, 35-70µ as the stationary phase and the solvents used were either of analytical grades or were distilled before use. Chiral HPLC was carried out using a Chiralpak AD column with appropriate mixtures of HPLC grade 2-propanol and hexane being used as eluent. Unless otherwise stated, Infrared spectra were obtained of dilute chloroform solutions. NMR spectra were obtained at the indicated spectrometer frequency as dilute solutions in CDCl3 at room temperature unless is otherwise stated. All coupling constants are reported in hertz (Hz). Highresolution mass spectra were obtained using either chemical ionization (CI, methane), fast atom bombardment (FAB), electron ionization (EI), or electrospray (ES) techniques. 1-(tert-Butyldimethylsilanyloxy)-3-(triphenylphosphanylidene)propan-2-one 21. n-Butyllithium (172 mL; 2.5 M in hexanes; 431 mmol) was added dropwise in four portions (3 × 50 mL and 1 × 22 mL), each over 5 min (with a 10 min interval between each addition), to a cool (0 °C) stirring suspension of Ph3PCH3‚Br (156 g; 437 mmol) in THF (1 L), and the resulting yellow/orange solution was stirred at 0 °C for a further 40 min. (O-TBS)methyl glycolate 209 (39.7 g 194 mmol) was added dropwise over 1 min, and the resulting mixture was then warmed to room temperature and stirred for a further 2 h. Water (600 mL) was added, and the mixture was stirred for 10 min before removal of the THF in vacuo. The resulting aqueous residue was partitioned between ethyl acetate (1.2 L) and water (600 mL), and the separated organic phase was dried (MgSO4) and concentrated in vacuo, giving a pale yellow solid. This material was purified by trituration with minimal ethyl acetate (×4), giving 21 as a white solid (61.0 g; 69%): mp 118-122 °C; δH (400 MHz) 0.14 (6H, s), 0.95 (9H, s), 4.14 (2H, s), 4.34 (1H, d, J 26.0), 7.42-7.46 (6H, m), 7.51-7.55 (3H, m), 7.65-7.70 (6H, m); δC (101 MHz, 303K) 192.1 (d, J 4.0), 133.0 (d, J 10.1), 132.0 (d, J 3.0), 128.7 (d, J 13.1), 127.1 (d, J 90.5), 68.2 (d, J 13.1), 49.0 (d, J 109.6), 26.3, 18.7, -4.9; δP (162 MHz, 303K) 17.5; m/z (ES+) 449.2070 (M + H, C27H34O2PSi requires 449.2066). Anal. Calcd for C27H33O2PSi: C, 72.3; H, 7.4. Found: C, 72.4; H, 7.3. (4R)-4-[4-(tert-Butyldimethylsilanyloxy)-3-oxobut-1enyl]-2,2-dimethyloxazolidine-3-carboxylic Acid tert-Butyl Ester 24. (S)-Garner’s aldehyde 9 (2.16 g; 9.42 mmol) was added dropwise over 2 min to a stirring solution of the ylide 21 (8.6 g; 19.2 mmol) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 3 days. Removal of the solvent in vacuo left the crude product, which was purified by column chromatography (4:1 pentane/diethyl ether) to give the enone 24 as a colorless oil (3.28 g; 87%): [R]D -60 (c 1.04, CHCl3) >95% ee (Chiralpak AD, hexane/i-PrOH (95: 5), 1 mL/min); νmax(film)/cm-1 1698, 1631; δH (400 MHz, C6D6, 343K) 0.15 (6H, s), 0.92 (9H, s), 1.36 (9H, s), 1.47 (3H, s), 1.61 (3H, s), 3.42 (1H, dd, J 9.0, 2.7), 3.65 (1H, dd, J 9.0, 6.5), 4.094.26 (1H, m), 4.13 (2H, app s), 6.46 (1H, d, J 15.8), 6.83 (1H, dd, J 15.8, 6.8); δC (101 MHz, C6D6, 343K) 197.6, 152.4, 145.6, 126.5, 95.2, 80.6, 69.8, 68.1, 59.3, 29.1, 27.6, 26.7, 24.9, 19.1, -4.7; m/z (ES+) 422.2357 (M + Na, C20H37NNaO5Si requires 422.2339). Anal. Calcd for C20H37NO5Si: C, 60.11; H, 9.33; N, 3.51. Found: C, 60.03; H, 9.36; N, 3.49. (4R)-4-[4-(tert-Butyldimethylsilanyloxy)-3-oxobutyl]-2,2-dimethyl-oxazolidine-3-carboxylic Acid tert-Butyl Ester 19. Palladium (341 mg, 10% on carbon) was added in one portion to a stirring solution of the enone 24 (301 mg; 0.75 mmol) in ethyl acetate (126 mL). The reaction vessel was purged with hydrogen by four evacuate/fill cycles, and the resulting mixture was stirred under an atmosphere of hydrogen (balloon) for 17 h. The catalyst was removed by filtration through a pad of Celite, and the filtrate was concentrated in vacuo to afford a yellow oil (2.17 g), which was purified by column chromatography (3:1 pentane/diethyl ether) to give 19 as a colorless oil (2.03 g; 80%): [R]D -18.1 (c 4.55, CHCl3) >95% ee (Chiralpak AD, hexane/i-PrOH (99:1), 0.5 mL/min); νmax/ cm-1 1713, 1682; δH (400 MHz, C6D6, 340 K) 0.03 (6H, s), 0.94 (9H, s), 1.42 (9H, s), 1.46 (3H, s), 1.65 (3H, s), 1.85-1.94 (1H,
7616 J. Org. Chem., Vol. 67, No. 22, 2002
m), 1.96-2.04 (1H, m), 2.27-2.42 (2H, m), 3.44 (1H, d, J 8.8), 3.62 (1H, dd, J 8.8, 6.0), 3.81 (1H, br s), 4.00 (2H, app s); δC (125 MHz, 1:1 mixture of rotamers) 210.0, 152.5, 151.9, 93.9, 93.4, 80.0, 79.7, 69.2, 67.0, 56.6, 34.9, 34.6, 28.4, 27.0, 25.8, 24.4, 23.1, 18.3, -5.5; m/z (FAB positive ion) 402.2646 (MH+, C20H40NO5Si requires 402.2676). Anal. Calcd for C20H39NO5Si: C, 59.8; H 9.8; N, 3.5. Found: C, 59.5; H, 9.5; N, 3.2. (4S)-2,2-Dimethyl-7-(tert-butyldimethylsilanyloxymethyl)-1-oxa-3-azaspiro[4.4]non-6-ene-3-carboxylic Acid tert-Butyl Ester 27. n-Butyllithium (6.17 mL, of a 2.1 M solution in hexanes, 13.0 mmol) was added dropwise over 11 min to a cold (-78 °C) stirring solution of trimethylsilyldiazomethane (7.50 mL of a 2 M solution in hexanes, 15.0 mmol) in THF (20 mL), and the resulting mixture was stirred for 1 h at -78 °C. The ketone 19 (3.92 g, 13.6 mmol) in THF (13 mL) was then added, dropwise over 20 min, and the mixture was stirred for another 70 min. The reaction mixture was warmed to 0 °C and stirred for 15 min. The reaction was quenched with NH4Cl (20 mL of a saturated solution diluted with water (25 mL)), extracted with ether (250 mL), dried (MgSO4), and concentrated in vacuo to give the crude product. Column chromatography [petroleum ether (40-60 °C)/Et2O (10:1)] afforded the pure product 27 (2.68 g, 69%) as a colorless oil: [R]D -49.0 (c 1.24, CHCl3); νmax/cm-1 1682; δH (400 MHz, C6D6, 340K) 0.28 (6H, s), 1.17 (9H, s), 1.62 (9H, s), 1.83 (3H, s), 1.87 (3H, s), 2.15 (1H, ddd, J 12, 8.7, 3.0), 2.30-2.40 (1H, m), 2.502.70 (2H, m), 3.83 (1H, d, J 8.7), 3.87 (1H, d, J 8.7), 4.31 (1H, d, J 13.8), 4.36 (1H, d, J 13.8), 5.63 (1H, s); δC (125 MHz, 2.3:1 mixture of rotamers) 152.1, 151.1, 146.3, 145.3, 126.6, 125.8, 94.8, 94.1, 79.4, 79.1, 74.3, 73.9, 73.7, 73.2, 62.4, 62.2, 35.0, 33.3, 30.7, 28.5, 26.9, 25.9, 24.5, 18.4, -5.3; m/z (ES+) 420.2523 (M + Na, C12H39NNaO4Si requires 420.2546). Anal. Calcd for C21H39NO4Si: C, 63.43; H, 9.89; N, 3.52. Found: C, 63.31; H, 9.82; N, 3.45. (4S,6R,7R)-6,7-Dihydroxy-2,2-Dimethyl-7-(tert-butyldimethylsilanyloxymethyl)-1-oxa-3-azaspiro[4.4]nonane-3carboxylic Acid tert-Butyl Ester 25. N-MethylmorpholineN-oxide (1.34 g; 9.91 mmol) was added in one portion to a room temperature stirring solution of the alkene 27 (1.31 g; 3.30 mmol) in acetone/water (10:1; 143 mL). K2OsO4‚2H2O (121 mg; 0.33 mmol) was added in one portion to the stirring mixture, and the resulting stirred at room temperature for a further 4.5 days. The reaction was quenched with Na2SO3 (1.26 g) and concentrated in vacuo, and the residue was adsorbed onto silica gel by evaporation from ethyl acetate (∼500 mL) to form a freeflowing powder. The dry powder was slurried in ethyl acetate and filtered through Celite, and the eluent was concentrated in vacuo, giving a dark yellow oil (1.47 g). This was purified by column chromatography (3:1 petrol/ethyl acetate), giving 25 as a colorless oil (1.34 g; 94%): [R]25D 41 (c 3.3, CHCl3) (97% ee, Chiralpak AD, 8:92 IPA/hexane); νmax(film)/cm-1 3454, 1694; δH (400 MHz, CD3C6D5, 368K) 0.07 (6H, s), 0.95 (9H, s), 1.47 (9H, s), 1.61 (3H, s), 1.67-1.56 (1H, m (obscured)), 1.67 (3H, s), 1.73-1.83 (1H, m), 1.96-2.06 (1H, m), 2.22 (1H, d (br), J 5.5 Hz), 2.33-2.43 (1H, m), 2.49 (1H, s), 3.55 (1H, d, J 9.8 Hz), 3.59 (1H, d, J 9.8 Hz), 3.72 (1H, d, J 9.2 Hz), 4.51 (1H, d, J 9.2 Hz), 4.80 (1H, s (br)); δC (126 MHz, C6D6, 340 K) 151.9, 94.3, 79.7, 78.5, 75.8, 71.2, 69.7, 31.4, 30.7, 30.2, 28.7, 26.5, 26.1, 18.5, -4.3; m/z (ES+) 454.2629 (M + Na, C21H41NNaO6Si requires 454.2601). (1S,3R)-1-tert-Butoxycarbonylamino-1,3-dihydroxymethylcyclopentane 28. Palladium (109 mg, 10% on carbon) was added to a solution of the unsaturated spirocycle 27 (870 mg, 2.19 mmol) in EtOAc (44 mL). The reaction vessel was purged with hydrogen by three evacuate/fill cycles, and the resulting mixture was stirred under an atmosphere of hydrogen (balloon) for 19 h. The catalyst was removed by filtration through a pad of Celite, and the filtrate was concentrated in vacuo to afford 26 (928 mg), which was used in the following reaction without further purification. HF (0.57 mL of 48% aqueous solution) was added in one portion to a stirring solution of crude 26 (927 mg) in CH3CN (23 mL), and the
Synthesis of (1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic Acid resulting solution was stirred for 15 min at room temperature before being quenched with excess NaHCO3 (30 mL of a saturated solution). The aqueous layer was extracted with Et2O (3 × 100 mL), dried (MgSO4), and concentrated in vacuo. Purification by column chromatography [petroleum (40-60 °C)/Et2O/MeOH gradient; (30:5:2)-(8:15:1)] afforded the diol 28 (451 mg; 81%) as a colorless oil: [R]D +6.9 (c 1.78, CHCl3); νmax /cm-1 3625, 3439, 1693; δH (400 MHz, C6D6, 343 K) 1.301.42 (2H, m), 1.39 (9H, s), 1.43-1.52 (1H, m), 1.54-1.63 (1H, m), 1.68-1.76 (1H, m), 1.78-1.89 (2H, m), 3.05 (1H, br s, OH), 3.21 (2H, app s), 3.47-3.60 (2H, m), 4.79 (1H, br s); δC (100 MHz) 156.0, 79.9, 68.8, 66.3, 64.9, 40.2, 38.5, 34.9, 28.4, 27.0; m/z (EI positive ion) 246.1688 (MH+, C12H24NO4 requires 246.1705). Anal. Calcd for C12H23NO4: C, 58.75; H, 9.45; N, 5.71. Found: C, 58.33; H, 9.56; N, 5.57. (1R,3S)-1-Aminocyclopentane-1,3-dicarboxylic Acid 1. CCl4 (0.48 mL), CH3CN (0.72 mL), and H2O (0.48 mL) were added successively to a mixture of NaIO4 (240 mg, 1.12 mmol) and RuCl3‚xH2O (62 mg, 0.30 mmol). After being stirred for 35 min, the mixture was added dropwise over 30 s to a cool (0 °C) stirring solution of the diol 28 (118 mg). After the mixture was stirred at 0 °C for 45 min, NaIO4 (534 mg, 2.54 mmol) was added in one portion, and the resulting mixture stirred at 0 °C for a further 3 h. The mixture was adsorbed onto silica, filtered through a pad of silica (EtOAc as eluent), and concentrated in vacuo giving the N-Boc-bis-carboxylic acid 29 as a colorless oil (111 mg) in crude form. HCl (concd, 2.5 mL) was added in one portion to a stirring solution of the crude N-Boc bis-carboxylic acid 29 in EtOAc (7.5 mL) and after 7 h at room temperature, the solution was concentrated in vacuo giving a yellow oil (106 mg). The crude material was dissolved in methanol (0.6 mL), and ethyl acetate (24 mL) and the
mixture was concentrated in vacuo until a white precipitate formed. The solid was removed by filtration and washed with cold (0 °C) EtOAc, giving a white powder (49 mg; 49%, 2 steps); δH (500 MHz, MeOH) 2.04-2.14 (2H, m), 2.19 (1H, dd, J 14.3, 8.3), 2.37-2.43 (1H, m), 2.61 (1H, dd, J 14.3, 8.3); δC (126 MHz; MeOH) 176.6, 174.0, 65.5, 45.1, 40.1, 36.7, 30.3. The hydrochloride salt was dissolved in NaOH (2M; 5 mL), washed with diethyl ether (4 mL, then 8 mL), and the aqueous acidified (HCl, 1M) to pH 5. Concentration in vacuo gave a white solid, which was purified by ion exchange chromatography (Dowex 50X8 200; 2M NH3 aq), giving ACPD 1 (24.9 mg; 30%, 2 steps from 28) as a white solid: mp 248 °C dec (lit.2c mp 246-250 °C dec); [R]29D -5.6 (c 1.3, H2O) (lit.2c [R]29D -6.9 (c 1.0, H2O)); δH (400 MHz, D2O) 1.93-2.07 (2H, m), 2.14 (1H, dd, J 14.5, 4.7), 2.21-2.36 (2H, m), 2.42 (1H, dd, J 14.5, 8.6), 3.03-3.11 (1H, m); δC (101 MHz, D2O) 186.7, 180.1, 69.7, 49.3, 42.5, 38.5, 32.8.
Acknowledgment. We thank The University of Botswana for the provision of a Scholarship (R.M.), the EPSRC and Pfizer Central Research for provision of a studentship (D.M.B.), and also AstraZeneca and the School of Chemistry, University of Nottingham, for additional financial support. Supporting Information Available: Experimental procedures for the preparation of 15, 16, 18, and 19. Copies of the 1H (500 MHz) and 13C (125 MHz) NMR spectra for our synthetic sample of 1. This material is available free of charge via the Internet at http://pubs.acs.org. JO025892V
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